tbuckley/cabot-search huggingface dataset:
Abstract 10603: Dapagliflozin Increases Ampk, Reduces Fibrosis/Hypertrophy and Nlrp-3, Il-6 and Galectin-3 Levels in Short-Term Doxorubicin-Treated Mice Improving Cardiac Function
Authors: Nicola Maurea, Simona Buccolo, Irma Bisceglia, Maria Laura L Canale, Antonio Luciano, Antonio Barbieri, Giuseppe Palma, Marino Scherillo, Vincenzo Quagliariello
Journal: Circulation (2022)

Introduction: Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to be of therapeutic value in patients with type 2 diabetes, chronic kidney disease, and heart failure with reduced ejection fraction (HFrEF), conditions that commonly coexist and are interrelated pathophysiologically. Hypothesis: Dapagliflozin (an SGLT2i), administered during doxorubicin, could improve cardiac function in preclinical models Methods: Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), DAPA at 12 mg/kg (DAPA, n=6) or doxorubicin combined to DAPA (DOXO-DAPA, n=6). Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd88, DAMPs (galectine 3 and calgranulinS100) , pAMPK, NF-kB, and 13 chemokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified through ELISA and western blot methods. Results: DAPA improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. A reduced expression of NLRP3, MyD88, DAMPs and NF-kB in cardiac tissues was seen in DOXO-DAPA group compared to DOXO mice (p&lt;0.001). Cardiac expression of IL-1β, IL-6, TNF-α, G-CSF and GM-CSF were significantly reduced after treatment with DAPA indicating anti-inflammatory properties. Expression of pAMPK was strongly enhanced in DAPA-DOXO compared to DOXO group. Levels of Calgranulin S100 and galectine-3 were strongly enhanced in DOXO group; on the other hand their expression were reduced by 47.7 and 52.3% in DAPA-DOXO group vs DOXO (p&lt;0.005). Hystology evaluation indicate reduction in hypertrophy, fibrosis and cardiac necrosis in DOXO-DAPA vs DOXO. Conclusions: DAPA is able to improve cardiac function and reduce biomarkers involved in heart failure and fibrosis. The overall picture of the study pushes the use of DAPA in prevention of cardiomyopathies induced by anthracyclines in cancer patients.
Abstract 10281: Meta-Analysis of Nitroglycerin’s Efficacy in Preventing the Incidence of Radial Artery Spasm and Occlusion During Trans-Radial Catheterization
Authors: Basel Abdelazeem, Mohamed T Abuelazm, Sarya Swed, Mohamed Gamal, Mostafa Atef, Mohamad Ashraf, Muhammad Atif Masood Noori, Anthony Lutz, Annabelle S Santos Volgman
Journal: Circulation (2022)

Introduction. Trans-radial artery (TRA) becomes the most common entry route for cardiac catheterization. However, it may cause radial artery spasm (RAS) and subsequent radial artery occlusion (RAO). We conducted a meta-analysis of randomized controlled trials (RCTs) to assess the efficacy of different administration routes of nitroglycerin in reducing RAS and RAO compared to placebo in adult patients undergoing TRA cardiac catheterization. Methods. We searched Google Scholar, Web of Science, SCOPUS, EMBASE, PubMed (MEDLINE), and CENTRAL for RCTs up to April 23, 2022. The outcomes of interest were the incidence of RAS or RAO. Pooled risk ratio (RR) with the corresponding 95% confidence interval (CI) in a fixed-effects model was generated using RevMan Software (Version 5.4). We evaluated heterogeneity using I-square and Chi-square tests. Results. Eleven trials with 5,814 patients were included. Compared to placebo, the overall results showed that nitroglycerin was effective in preventing RAS (RR: 0.71 with 95% CI [0.59, 0.84], p= 0.0001), and RAO (RR: 0.74 with 95% CI [0.58, 0.94], p= 0.02). However, subgroup analysis according to the route of administration showed statistically significant result with subcutaneous nitroglycerin in prevention both RAS (RR: 0.57 with 95% CI [0.43, 0.77], p= 0.0003) and RAO (RR: 0.39 with 95% CI [0.16, 0.98, p= 0.05) but not intra-arterial nitroglycerine for RAS ((RR: 0.8 with 95% CI [0.63, 1.02], p= 0.07) and RAO (RR: 0.78 with 95% CI [0.6, 1.01], p= 0.06)), neither topical nitroglycerine for RAS ((RR: 0.73 with 95% CI [0.42, 1.24], p= 0.24). Conclusion. Our meta-analysis showed that subcutaneous nitroglycerin administration for TRA catheterization may prevent RAS and subsequent RAO compared to placebo. In contrast, intra-atrial and topical nitroglycerin have non-significant outcomes. Figure 1: Forest plot of the primary outcomes sub-grouped by route of administration (A- RAS, B- RAO). I2: I-squared; CI: confidence interval.
Abstract 10735: Brash Syndrome: Frequently Under-Recognized and Often Confused With Simple Hyperkalemia
Authors: Kunal N Patel, Betsy a Joseph, Ankit Bansal, Aadhithyaraman Vaithiya Santharaman, Andrea Santos Argueta, Avleen kaur, Vyoma Patel, Karandeep Singh, Keval V Patel, MD
Journal: Circulation (2022)

Introduction: BRASH syndrome is a relatively newly recognized and under-reported clinical entity characterized by bradycardia, renal dysfunction, atrioventricular node blockade (AVNB), shock, and hyperkalemia. We report a case of BRASH syndrome that was refractory to medical therapy alone, requiring transvenous pacing, hemodialysis, and vasopressor support. Case presentation: An 82-year-old female with hypertension, diabetes, and paroxysmal atrial fibrillation (on metoprolol and verapamil) was found unresponsive at a nursing home. She had refractory shock (99/34 mmHg) and symptomatic bradycardia with heart rate (HR) of 33 BPM. EKG showed atrial fibrillation rhythm with ventricular rate of 31 BMP and peaked T-waves. Labs revealed creatinine of 1.98 mg/dL, potassium of 6.8 mmol/L, and TSH of 2.90 ulU/ml. She had no signs of infection and echocardiogram showed normal left ventricular systolic function. She was intubated for airway protection. AVNB agents were immediately held. Potassium-lowering agents and vasoactive drugs were administered. Temporary transvenous pacemaker was placed due to persistent bradycardia with hemodynamic instability even after transcutaneous pacing. Temporary hemodialysis was started for worsening renal failure and refractory hyperkalemia. She was weaned off vasopressor support, mechanical ventilation, hemodialysis and temporary pacing over the next few days. Renal function improved and HR stabilized at 70 BPM. Discussion: In our case, AVNB agent overdose caused bradycardia which in turn led to decreased cardiac output and renal hypoperfusion. Resultant acute kidney injury led to decreased clearance of renally excreted metoprolol and verapamil and worsening hyperkalemia, which locked the patient in a vicious cycle of BRASH syndrome leading to hemodynamic compromise. Therefore, rapid diagnosis and correct management with transvenous pacemaker and renal replacement therapy are crucial to reduce mortality.
Abstract 10468: International Classification of Diseases (ICD) Codes for Congenital Heart Defects (CHD) Have Variable and Limited Accuracy for Detecting CHD Cases
Authors: Lindsey C Ivey, Fred H Rodriguez, Haoming Shi, COHEN CHONG, Joy Chen, Cheryl L Raskind-Hood, Sherry Farr, Karrie F Downing, Wendy M Book
Journal: Circulation (2022)

Introduction: Administrative data permit analysis of large cohorts but rely on ICD-9-CM and ICD-10-CM billing codes that may not accurately identify CHD cases. Variables that may improve accuracy are unknown, yet improved accuracy will improve CHD surveillance. Methods: We validated 1500 cases with an encounter between 1/1/2010 - 12/31/2019 identified by at least one of 90 CHD codes (41 ICD-9-CM, 49 ICD-10-CM) in 2 healthcare systems (1 adult, 1 pediatric), through medical record review and chart abstraction for presence of a CHD. Inter- and intra-observer reliability exceeded 93%. Results: Positive predictive value (PPV) of ICD codes for CHD (Figure 1) was 68.0% (1020/1500) overall, 95.7% (247/258) for severe codes, 52.8% (371/703) for shunt codes, 75.2% (243/323) for valve codes, 73.2% (120/164) for shunt and valve codes, and 75.0% (39/52) for a select group of 7 codes in ‘other’ category. PPV for cases with &gt; 1 unique CHD code was 73.1% (920/1259) vs. 41.5% (100/241) for cases with only 1 unique CHD code. Characteristics of cases with and without CHD are in Table 1. ICD code 745.5/Q21.1 in isolation was present in 2.2% of cases with confirmed CHD vs. 19.4% of cases without CHD (p&lt; 0.0001). Median number of encounters with a CHD code was higher in cases with CHD (6) vs. without CHD (2), p&lt; 0.0001. Patent foramen ovale was present in 65.8% of false positives (316/480). Conclusion: There is significant variability in the PPV of individual and groups of CHD codes for detection of CHD. The presence of a code for severe CHD is associated with high PPV for true CHD. Use of administrative data for CHD surveillance may require the development of algorithms to improve the accuracy of case detection.
Abstract 10019: Access to Specialty Cardiovascular Care and Uptake of Cardioprotective Anti-Hyperglycemic Agents Among Adults With Type 2 Diabetes: A Cohort Study
Authors: Arash Aghajani Nargesi, Callahan Clark, Mengni Liu, Abraham Reddy, Sam Amodeo, Rohan Khera
Journal: Circulation (2022)

Background: Sodium glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) are the only cardioprotective anti-hyperglycemic medications, but have had limited use. We evaluated whether access to specialty cardiovascular care improves the uptake of these cardioprotective medications in type 2 diabetes (T2D). Methods: In a retrospective cohort study between Jan 2019 and Dec 2020, beneficiaries with Medicare Advantage or commercial insurance were followed using Optum Labs’ de-identified administrative claims for the initiation of SGLT-2i and GLP-1RA among eligible adults with T2D across specialty visits. Eligibility included atherosclerotic cardiovascular disease (ASCVD), heart failure, or diabetic nephropathy for SGLT-2i and ASCVD for GLP-1RA. Detailed demographic and comorbidity information was obtained from the year before cohort enrollment. Results: Among eligible individuals for SGLT-2i (N=294,988) and GLP-1RA (N=198,525), 10.4% and 16.7% initiated these medications during the study period, respectively. Overall, 57% of those with an indication for SGLT-2i and 64% for GLP-1RA had at least one visit with a cardiologist. After accounting for differences in clinical characteristics and comorbidities, those with a visit with a cardiologist had higher odds of initiating SGLT-2i (OR = 1.26 [1.21-1.30]) and GLP-1RA (OR=1.05 [1.01-1.10]). However, these were not higher than those receiving care from family medicine and internal medicine providers and were substantially lower than those receiving care from an endocrinologist (Figure). Conclusion: In 2019-2020, among insured individuals with compelling CV indications, despite broad access to cardiovascular care, receiving care from cardiologists was only modestly associated with uptake of novel therapies. Efforts to improve the use of these medications are less likely to benefit from efforts to broaden access to specialty cardiovascular care.
Abstract 10083: Cardiovascular Outcomes of Non-ST-Elevation Myocardial Infarction (NSTEMI) Patients Without Standard Modifiable Risk Factors (SMuRF-less): The Intermountain Healthcare Experience
Authors: Jeffrey L Anderson, Stacey Knight, Heidi T May, Viet T Le, Tami L Bair, Kirk U Knowlton, Joseph B Muhlestein
Journal: Circulation (2022)

Introduction: Recent interest has focused on STEMI patients (pts) without standard modifiable risk factors (SMuRF-less), noting that they are surprisingly common (14-27%). These studies have reported them to have a worse, or at best similar, in-hospital/short-term prognosis. However, relatively little attention has been paid to the prevalence and prognosis of SMuRF-less patients with non-ST elevation myocardial infarction (NSTEMI). The aim of our study was to identify the proportion and outcomes of SMuRF-less NSTEMI pts in a large US healthcare population. Methods: Pts with NSTEMI between 2001-2021 presenting to Intermountain Healthcare catheterization laboratories were included. SMuRF included a clinical diagnosis of, or treatment for, hypertension, hyperlipidemia, diabetes, and/or smoking. 60-day and long-term major adverse cardiovascular event (MACE) outcomes were defined as death, myocardial infarction, and heart failure hospitalization and were tested using Cox proportional hazard regression. Results: NSTEMI pts totaled 8196, of which1458 (17.8%) were SMuRF-less. SMuRF-less pts were younger, more frequently male, had fewer comorbidities, and were slightly less likely to have PCI/CABG than NSTEMI pts with SMuRF (Table 1). 60-day MACE for SMuRF-less pts were lower (adj HR 0.55, p&lt;0.0001), and this persisted for long-term MACE outcomes (adj HR 0.64, p&lt;0.0001) and for each of its components (Table 2). Conclusions: In this large US healthcare population, SMuRF-less NSTEMI presentation, as with STEMI presentation, was found to be common (17.8%). However, unlike STEMI reports, short- and long-term outcomes were generally more favorable for SMuRF-less status. Further studies to increase understanding of risk factors and preventive measures for NSTEMI in SMuRF-less pts are indicated.
Abstract 10474: Long-Term Daily Activity is Associated With Exercise Capacity and Quality of Life in Pulmonary Arterial Hypertension
Authors: Andrew M Hughes, Jeffrey Annis, Anna R Hemnes, Alisha Lindsey, Kelly Burke, Evelyn M Horn, Evan Brittain
Journal: Circulation (2022)

Introduction: Reduced functional capacity is a hallmark of pulmonary arterial hypertension (PAH). Six minute walk distance (6MWD) is a common measure of functional capacity. Unlike the 6MWD, daily activity monitoring integrates behavioral aspects of physical capacity. We hypothesized that daily activity is associated with 6MWD and quality of life (QOL) in patients with PAH. Methods: This study included patients with PAH from the NHLBI-funded Pulmonary Vascular Disease Phenomics (PVDOMICS) study. PVDOMICS collected 6MWD and QOL surveys (Minnesota Living with Heart Failure [MLHF] and Short Form-36 [SF-36]) data. Daily activity was measured using Fitbit devices which participants wore continuously for 12 weeks. Daily activity was expressed as average daily steps and graded intensity. Results: We enrolled 45 patients with PAH (age, 48.1 + 13.4 years) with median daily steps of 4146 (IQR: 2682-6977). Sedentary, fairly active, and very active minutes/day were 850 (IQR: 774-1093), 5.0 (IQR 2.0-7.6), and 2.1 (IQR 0.7-7.3). The median time between 6MWD and the start of daily activity monitoring was 32 days (IQR 11-53). Average daily steps correlated with 6MWD (r = 0.70, p&lt;0.001), MLHF total score (r = - 0.46, p=0.002), MLHF physical and emotional domains, and the SF-36 physical component score. Among hemodynamic measures, average steps and fairly active minutes were most strongly associated with PA compliance (r=0.46 and r=0.64; both p&lt;0.05). In contrast, 6MWD only correlated with the SF 36 physical component but no MLHF measures. Conclusions: In a geographically diverse PAH cohort, long-term daily step counts are associated with exercise capacity and QOL. Daily activity measures capture behavioral information not captured by the 6MWD and correlated with prognostic hemodynamic measures. Daily activity monitoring and 6MWD represent complementary measures for the assessment of functional capacity in patients with PAH.
Abstract 10904: Integrins Signaling Represents an Exciting Therapeutic Avenue to Counter Vascular Remodeling and Right Ventricular Failure in Pulmonary Arterial Hypertension
Authors: Sarah-Eve Lemay, Mónica S Montesinos, Yann Grobs, Tetsuro Yokokawa, Tsukasa Shimauchi, Sandra Breuils Bonnet, Sandra Martineau, MABROUKA SALEM, Alice Bourgeois, Charlotte Romanet, XINQIANG HUANG, James Dowling, Min Lu, Adrian Ray, Francois Potus, Steeve Provencher, Olivier Boucherat, Sebastien Bonnet
Journal: Circulation (2022)

Pulmonary arterial hypertension (PAH) is characterized by progressive obstruction of pulmonary arteries (PAs), culminating in right ventricular (RV) failure and premature death. Like cancer cells, PA smooth muscle cells (PASMCs) isolated from PAH patients exhibit exaggerated proliferation and resistance to apoptosis in response to extracellular matrix remodeling. Integrins, members of the cell adhesion receptors superfamily, are known to promote cell proliferation, survival, hypertrophic growth and fibrosis, which are key elements contributing to PAs remodeling and RV failure. Therefore, we hypothesized that integrins signaling could promote PAH-PASMC proliferation and resistance to apoptosis contributing to PAs vascular remodeling, and RV maladaptive hypertrophy and fibrosis, leading to RV failure. Using NanoString, we found that members of the fibronectin-binding integrin (FiBI) family were the most abundantly expressed in PASMCs and RV fibroblasts (RVFbs) isolated from PAH patients. By western blot (WB), we showed that FiBIs expression is significantly changed in distal PAs, PASMCs, PA endothelial cells and decompensated RV from PAH patients compared to controls (p&lt;0.05). In vitro , pharmacological inhibition of FiBIs decreases PAH-PASMCs proliferation (WB: PLK1; Ki67 labeling; p&lt;0.05, n=5) and resistance to apoptosis (WB: Survivin; Annexin V labeling; p&lt;0.05, n=5). These effects were associated with a decreased activation of FiBIs downstream signaling, FAK and MAPK pathways. In adult rat cardiomyocytes and human RVFbs, FiBIs inhibition decreases phenylephrine-induced hypertrophy (f-actin labeling; p&lt;0.001) and TGFβ1-induced RVFb activation (WB: αSMA, and Col1; p&lt;0.05). In vivo , in both moncrotaline and sugen/hypoxia rats with established PAH, pharmacological inhibition of FiBIs alone or in combination with macitentan and tadalafil improves hemodynamic (mPAP, CO, TAPSE, RVFAC; p&lt;0.05) and vascular remodeling (EVG; p&lt;0.01). In the PA banding rat model, inhibition of FiBIs attenuates RV failure (CO, TAPSE, RVEDP, RVFAC; p&lt;0.01). Our results suggest that integrins play a key role in the pathophysiology of PAH in both the lungs and the RV. Their inhibition provided significant beneficial effects both in vitro and in vivo .
Abstract 10922: Maternal Hypercholesterolemia Induces Changes in DNA Methylation Pattern of Lipid Metabolism Genes in the Human Placenta
Authors: JAYALEKSHMI VS, BUDHADITYA BASU, SURYA RAMACHANDRAN
Journal: Circulation (2022)

Introduction: Maternal hypercholesterolemia (MHC) during gestation is reported to enhance formation of fatty streaks in human fetuses leading to atherosclerosis in their adulthood. As maternal lipid levels increase during gestation as a normal physiological response to growing fetus, cholesterol levels are not routinely monitored in the outpatient clinic. The mechanisms mediating the stimulus transferred from hypercholesterolemic mothers to the fetus resulting in atherogenesis remains to be delineated. Hypothesis: We hypothesize that high lipid levels of hypercholesterolemic mother program the fetus by causing changes in DNA methylation patterns of lipid transport and metabolism genes in the placenta. Methods: Pregnant females within 100 days of first pregnancy were recruited. Total cholesterol (TC) and Low Density Lipoprotein (LDL) levels above 200mg/dL and 130mg/dL respectively were considered as hypercholesterolemic (MHC; n=50). Pregnant mothers with normal cholesterol levels were also recruited (NC; n=50). Lipid profiling of maternal blood was performed in all trimesters. Cord blood at the time of birth and neonatal blood on the 2 nd day post birth were also profiled. DNA methylation array was performed in the placenta of MHC and NC mothers post delivery. Data were analyzed using RnBeads and Limma package. Data were validated by qRT PCR and immunohistochemistry of placental tissues. Results: Lipid profiling revealed high TC and LDL levels in MHC mothers and high triglycerides in their neonates on the 2 nd day post birth. There were 3789 differentially methylated gene sets reported in the placenta of hypercholesterolemic mothers of which, 167 genes were hypomethylated and 94 genes were hypermethylated in the CpG islands. The hypermethylation and downregulation of lysosomal lipase genes (LIPA) was observed in the placenta of MHC mothers. This was complemented by upregulated expression of PEX11A, a peroxisomal biogenesis factor and ABCD1 which is a fatty acid transporter. Conclusions: We report the hypermethylation of lysosomal lipid degradation genes and hypomethylation of peroxisomal genes in the placenta of MHC mothers. This results in high triglycerides in neonates with a risk for early atherogenesis in adulthood.
Abstract 10851: A Randomized Study to Compare LDL-C-Lowering Effects of Inclisiran With Usual Care vs Usual Care Alone in Patients With Recent Hospitalization for an Acute Coronary Syndrome: Rationale and Design of the VICTORION-INCEPTION Trial
Authors: Jeffrey L Anderson, Ann M Navar, Neerja Balachander, Jason Lecocq, Nihar R Desai, Kirk U Knowlton
Journal: Circulation (2022)

Introduction: Patients are at high risk for a recurrent cardiovascular (CV) event in the first year following acute coronary syndrome (ACS). Low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for recurrent CV events. Despite the availability of lipid-lowering therapies (LLT), many patients fail to achieve guideline recommended LDL-C &lt;70 mg/dL in the year post-ACS. Early LDL-C evaluation and LLT intensification after recent ACS may reduce recurrent CV event risk. In prior phase III trials, inclisiran plus maximally tolerated statin therapy effectively reduced LDL-C in patients with established ASCVD. As patients with an ACS within 3 months of screening were excluded from these trials, the efficacy of inclisiran in these patients is unknown. Objective: To assess the LDL-C-lowering effect of inclisiran with usual care vs usual care alone in patients with recent ACS and LDL-C ≥70 mg/dL, despite statin therapy. Methods: VICTORION-INCEPTION (NCT04873934) is a phase IIIb, randomized, parallel-group, open-label, multicenter, US-based trial enrolling eligible patients to receive inclisiran plus usual care or usual care ( Figure ). Concomitant LLT and routine LDL-C assessment is at the discretion of the managing physician to mimic real-world clinical practice. The primary endpoints are percent change from baseline in LDL-C and proportion of patients achieving LDL-C &lt;70 mg/dL. Key secondary endpoints include absolute change from baseline in LDL-C by visit, proportion of patients reaching pre-specified LDL-C targets, other plasma lipids, adherence to background LLT, and safety and tolerability of inclisiran. Exploratory endpoints include patient-reported outcomes and healthcare resource utilization. Conclusions: VICTORION-INCEPTION, an ongoing trial planned to complete in early 2024, will assess the effectiveness of inclisiran plus usual care for the management of patients with elevated LDL-C post-ACS despite receiving statin therapy.